MANEJO ACTUAL DEL PACIENTE CON CPNM CON REORDENACIONES ALK/ROS O MUTACIONES EN EGFR Rosario García Campelo Complejo Hospitalario Universitario A

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1 MANEJO ACTUAL DEL PACIENTE CON CPNM CON REORDENACIONES ALK/ROS O MUTACIONES EN EGFR Rosario García Campelo Complejo Hospitalario Universitario A Coruña

2 The seventies IMAGINE

3 The eighties

4 The Ninety

5 2000 s: The beginning of personalized history in NSCLC

6 THE SHADOWS EGFR TKI, STATE OF THE ART threshold of efficacy Chemotherapy 1 st and 2 nd Generation EGFR TKI Schiller NEJM 2002 * Reguart Future Oncol 2015

7 CAN WE DO IT BETTER?

8 EGFR mutation testing and receiving test results before starting 1 st line therapy - EU For approx. two thirds of Italian, Spanish and UK NSCLC patients in first line therapy results of the test on EGFR mutation were available before physicians decided on treatment; lower shares in Germany (52%) and France (40%). 1L advanced/metastatic (stage IIIb/IV) NSCLC patients managed in last 3 months Europe n = 251 n = 50 n = 50 n = 50 n = 50 n = 51 % 1 st line NSCLC patients Not tested before 1 st line therapy Tested but tests results not available before decision on 1 st line treatment (calculated) Test results available before decision on 1 st line treatment (calculated) F** D F** D F** D F ** Sig testing only on available before decision! BASE: Q3: All physicians; Q3a: Physicians with patients tested on EGFR mutation BEFORE administration of first-line therapy? ** Statistically significant ELCC 2015

9 CAN WE DO IT BETTER? 1 st vs 2 nd generation EGFR TKIs 3 rd generation EGFR TKIs Novel combinations Role of IO

10 Estimated PFS probability Lux-LUNG 7 PFS by independent review Afatinib (n=160) Gefitinib (n=159) Median PFS (months) HR (95% CI) 0.73 ( ) p value No. of patients Afatinib Gefitinib % p= % p= % 8% Time (months)

11 Estimated OS probability Lux-LUNG 7 OS in the overall population and patient subgroups Afatinib (n=160) Gefitinib (n=159) Median, mo HR (95% CI) p-value 0.86 ( ) Factors N HR (95% CI) Total ( ) EGFR mutation L858R Del ( ) 0.83 ( ) 0.6 Brain metastases Absent Present ( ) 1.16 ( ) No. at risk: Afatinib Gefitinib Time (months) Baseline ECOG PS Gender Age Race Smoking history 0 1 Male Female <65 years 65 years Non-Asian Asian Never smoked Light ex-smoker Other current/exsmokers ( ) 0.75 ( ) 0.80 ( ) 0.88 ( ) 0.66 ( ) 1.22 ( ) 0.78 ( ) 0.95 ( ) 0.92 ( ) 1.12 ( ) 0.63 ( ) Median follow-up: 42.6 months (as of 08 April 2016) Favours afatinib 1/4 1 4 Favours gefitinib Park D, et al. WCLC 2017

12 Probability of PFS DACOMITINIB ARCHER 1050 PFS: Blinded Independent Review (ITT population) PFS rate 30.6% vs 9.6% Number of Events, n (%) Median PFS (95% CI) HR (95% CI) Daco (N=227) 136 (59.9%) 14.7 (11.1, 16.6) Gef (N=225) 179 (79.6%) 9.2 (9.1, 11.0) 0.59 ( ) P< Censored No. at risk Months Dacomitinib Gefitinib Tony Mok, et al. ASCO 2017

13 Ramalingam S et al. ELCC 2016 Osimertinib (AZD9291) as first-line treatment for EGFR mutation-positive advanced NSCLC: updated efficacy and safety results from two Phase I expansion cohorts FLAURA PHASE III TRIAL

14 LET S THINK DIFFERENT Targeting genetic defects in a personalized strategy with a single targeted agent is limited by the high degree of intra-tumor heterogeneity, complexity and adaptation of cancer-cell signaling networks and high somatic mutation rates in cancer.

15 WHAT REALLY MATTERS THE CLINICAL EVIDENCE

16 JO25567: randomised phase II study of first-line bevacizumab + erlotinib vs erlotinib in EGFR Mut+ NSCLC Stage IIIB/IV or recurrent NSCLC Non-squamous histology EGFR Mut+ Exon 19 deletion/l858r No prior treatment ECOG PS 0 1 (n=154*) R Erlotinib 150mg/day (n=77) Bevacizumab 15mg/kg i.v. q3w + erlotinib 150mg/day (n=75) JO29424 noninterventional follow-up study investigating OS Endpoints 1 PFS (IRC) 2 OS, ORR, DCR, QoL, safety Exploratory endpoint: biomarker assessment *Two patients withdrew before treatment started and were excluded Seto, et al. Lancet Oncol (11):

17 PFS probability JO25567: bevacizumab + erlotinib is superior to erlotinib Bevcizumab + erlotinib (n=75) Erlotinib (n=77) HR 0.54 ( ) Log-rank p= Time (months) 68% maturity (bevacizumab + erlotinib: 46/75 events; erlotinib: 57/77 events) Seto, et al. Lancet Oncol (11):

18 BELIEF: first-line bevacizumab + erlotinib in EGFR Mut+ NSCLC Non-squamous NSCLC Stage IIIB-IV or postoperative recurrence Chemotherapy-naive Activating EGFR mutations - exon 19 deletion / L858R ± T790M Brain metastases allowed (n=109) Bevacizumab 15mg/kg i.v. q3w + erlotinib 150mg/day PD Endpoints 1 PFS (IRC) 2 OS QoL Response rate Safety Stahel, et al. ECC 2015 (Abs 3BA)

19 BELIEF: PFS by T790M mutation (N=109) Events/N Median PFS (95%CI) 12m PFS (95%CI) All 57/ m ( ) 56.7% ( ) T790M+ 15/ m (13.1-NE) 72.4% ( ) T790M- 42/ m ( ) 49.4% ( ) Stahel, et al. ECC 2015 (Abs 3BA)

20 Afatinib Erlotinib Gefitinib A+E/G Dacomitinib

21 Checkpoint inhibitors in metastatic EGFR mutated NSCLC cancer. A meta-analysis Khoon C, et al. J Thorac Oncol 2016

22 High CD73 expression correlates with Low PD-L1 protein expression Rizvi N et al. ASCO 2017

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24 PERSONALIZED SELECTION OF 1ST LINE THERAPEUTIC OPTION IN EGFR MUTANT NSCLC: 2017 OPTIONS Erlotinib Gefitinib PS Age Comorbilities Patient preferences Expected toxicity Cost Afatinib 1 st -/2 nd -G TKI + Avastin

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26 Clinical & Molecular Heterogeneity of Acquired Resistance Diverse Molecular Mechanisms of Acquired Resistance Diverse Clinical Patterns of Progression Yu, H, et al. CCR 2013, Gandara D., Clinical Lung Cancer 2014

27 Probability of PFS IMPRESS trial: Comparison of PFS between Pt doublet and Pt doublet + gefitinib in EGFR+ patients who failed EGFR-TKI after response IMPRESS design PFS Gefitinib (n=133) Placebo (n=132) Stage IIIB/IV NSCLC EGFR mutation positive WHO PS 0 1 Achieved response* with first-line gefitinib PD <4 weeks prior to study (n=265) R 1:1 Soria et al., Lancet Oncol, 2015 Gefitinib 250 mg + cisplatin 75 mg/m 2 + pemetrexed 500 mg/m 2 up to 6 cycles (n=133) Placebo + cisplatin 75 mg/m 2 + pemetrexed 500 mg/m 2 up to 6 cycles (n=132) Gefitinib (n=81) Placebo (n=61) Plasma T790M+(N=142) HR = 0.97 (0.67, 1.42); p= HR 0.86 (0.65, 1.13); p=0.273 plasmat790m- (N=105) Gefitinib (n=46) Placebo (n=59) HR = 0.67 (0.43, 1.03); p= Mok et al., WCLC 2015

28 Acquired resistance to EGFR TKI AXL inhibition INC280 Cabozantinib Crizotinib Plat-VP16 Camidge Nature Rev 2014

29 Osimiertinib Phase I and Phase II studies AURA Phase II ORR: 62% mpfs: 12.3 Yang J, et al. J Clin Oncol 2017

30 Mok et al. NEJM 2016 AURA 3

31 Brain activity AURA 3 ORR 70% vs 31% Tumor response in CNS evaluable for <br />response set Presented By Maria Garrassino at 2017 ASCO Annual Meeting

32 CNS mpfs: 11.7m vs 5.6m Slide 12 Presented By Maria Garrassino at 2017 ASCO Annual Meeting

33 OSIMERTINIB IS THE STANDARD OF CARE IN THOSE PROGRESSING EGFR MUTANT ADVANCED NSCLC HARBORING T790M

34 ALK translocation: biological relevance Cromosona 2p32.2 Proteina transmembrana con actividad TK AKT PI3K STAT3/5 RAS PLC En adultos, la expresión normal se limita al sistema nervioso BAD Supervivencia mtor MEK PIP2 S6K LrK IP3 Proliferación celular Grande E et al. Mol Cancer Ther 2011 Bai et al. Mol Cell Biol 1998 Mossé et al. CCR 2009.

35 THE REASON FOR ALK TESTING SEEMS QUITE CLEAR Line of therapy Ph I (1001) n = 149 Any line 32 % 2 nd line Ph II (1005) n=261 2 nd and beyond 6,6 % 2 nd line Ph III (1007) n= 172 (crizo arm) Ph III (1014) N=172 (crizo arm) 2 nd line 1 st line ORR % ,3 74 Median duration of response 48.1 wks 41.9 wks 36 wks 49 wks Median duration of treatment 43.1 weeks 48 weeks 30 weeks NR Median PFS 9.7months 8.1 months 7.7 months 10.9 months Survival probability At 12 months 81% NA 70% 84%

36 ADDRESSING ALK+ NSCLC IS MORE THAN A 1 ST LINE DECISSION

37 SEQUENCING ALK INHIBITORS WORKS

38 SEQUENCING ALK INHIBITORS WORKS Activity of ALK inhibitors in crizotinib treated patients Drug Study RR mpfs Ceritinib 1,2;8 Phase I ASCEND-1 Phase II ASCEND-2 Phase III ASCEND-3 56% 38.6% 39.1% Alectinib 3,4,5 Phase I/II AF-001JP Phase II NP28761 Phase II NP % 48% 50% NA NA 10.3 Brigatinib 6 Phase I/II 76% 12.9 Lorlatinib 7 Phase I/II 47% 11.4 Ensartinib 9 Phase I/II 64% NA 1. Kim DW et al. Lancet Oncol Mok T et al. J Clin Oncol 2015 Abstr Seto T et al. Lancet Oncol Shaw A et al. Lancet Oncol Ou SH et al. J Clin Oncol Bazhenova et al. ESMO Solomon et al. ASCO Scagliotti G et al. ESMO Horn et al. ESMO 2016

39 LORLATINIB in ALK + Patients Previously Treated With 1 ALK TKI Total (EXP2 5) (n=82) EXP2 Prior CRZ (n=7) EXP3 1 Prior TKI a (n=18) EXP4 2 Prior TKIs (n=44) b EXP5 3 Prior TKIs (n=13) Best overall response, n Complete response (%) c Partial response Stable disease Progressive disease Indeterminate 1 (1.2) 26 (31.7) 27 (32.9) 17 (20.7) 11 (13.4) 0 (0.0) 4 (57.1) 1 (14.3) 2 (28.6) 0 (0.0) 0 (0.0) 8 (44.4) 5 (27.8) 3 (16.7) 2 (11.1) 1 (2.3) 10 (22.7) 18 (40.9) 9 (20.5) 6 (13.6) 0 (0.0) 4 (30.8) 3 (23.1) 3 (23.1) 3 (23.1) ORR, n (%) c 27 (32.9) 95% CI d (57.1) (44.4) (25.0) (30.8) DCR at 12 weeks, n (%) c 46 (56.1) 95% CI d (71.4) (61.1) (54.5) (46.2) a Prior CRZ + chemotherapy or 1 other ALK TKI ± chemotherapy; b One patient in EXP-4 was excluded from the intention-to-treat population due to lack of documentation of ALK gene rearrangement; c By independent central review; d Using exact method based on binomial distribution. Duration of response data were not mature ALK, anaplastic lymphoma kinase; CI, confidence interval; CRZ, crizotinib; DCR, disease control rate; ORR, objective response rate; TKI, tyrosine kinase inhibitor. Sai-Hong Ignatius Ou et al. ASCO 2017

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41 Progression-free Survival (%) ALEX Phase III trial Primary endpoint:pfs, investigator-assessed Crizotinib (N=151) Alectinib (N=152) 60 Alectinib Patients with events, n (%) 102 (68) 62 (41) 40 NR Median PFS, months (95% CI) 11.1 ( ) NR (17.7 NR) months Crizotinib HR (95% CI) P-value (logrank test) 0.47 ( ) P< No. at Risk Crizotinib Alectinib Day Months Alice T. Shaw, et al. ASCO 2017

42 Shaw et al, ALEX: PFS underpinned by CNS activity Presented By Sanjay Popat at 2017 ASCO Annual Meeting

43 Reordenamiento de ROS1 Four new fusion partners (CLTC, LIMA1, MSN, TMEM106B) Similar perfil clínicopatológico que pacientes ALK+ Gainor JF et al. The Oncologist 2013; Bergethon K et al. J Clin Oncol 2012; Davies KD et al. Clin Cancer Res 2012; Yoshida A et al. Am J Surg pathol 2013; Scheffler M et al. Oncotarget 2015; Tsao AS et al. J Thorac Oncol 2016; Zhu Q et al. Transl Lung Cancer Res 2015

44 Why should we test for Ros1?

45 TARGETING ROS: PROFILE 1001 N= 53 RR: 69.8% Median PFS, months 95% CI , NR NR, not reached a Data as of cutoff date of 30 November Shaw A et al. ESMO 2016

46 The US and European experience RR 72% 80% PFS Shaw A, et al. NEJM 2014 Mazieres J et al. J Clin Oncol 2015

47 Progression-free survival (%) EUCROSS TRIAL (A) Waterfall plot of best response (N=29) Partial response (PR) Stable disease (SD) Progressive disease (PD) (B) Kaplan-Meier chart of progression-free survival (N=29) (N=30) ORR DCR PD % (N; 95% CI) 66.7 (20; ) 83.3 (25; ) 13.3 (4; ) 20 0 (N=30) Med. PFS Longest PFS Time (months) months (95% CI) NR 23.8 NE 3.3 (1; ) Med. FU 13.3 ( ) Sebastian M, et al. WCLC 2016 *Investigator assessed

48 Phase II trial Crizotinib in Ros1 advanced NSCLC Objective response rate, n (%) 88 (69.3) 95% CI 60.5, 77.2 Best response, n (%) Complete response 14 (11.0) Partial response 74 (58.3) Median TTR, months 1.9 Range Disease control rate, % (95% CI) 8 weeks 88.2 (81.3, 93.2) 16 weeks 80.3 (72.3, 86.8) Median PFS, a months % CI 10.3, NR Probability of survival, b % (95% CI) 6 months 92.0 (85.7, 95.6) The overall ORR met the prospectively-defined clinically-meaningful threshold (lower bound of two-sided 95% CI >30%) Median duration of response was not reached by the data cutoff date; however, responses were durable, as the lower limit of the 95% CI around the estimated duration of response was 8.5 months 12 months 84.4 (75.9, 90.2) Goto K, et al. ASCO 2016

49 Single arm trials with Crizotinib in TKI-naïve ROS1 + Trial Number (n) Region ORR PFS (mo) OS 12 mo PROFILE World 69% % EUROS Europe 80% % AcSé 3 37 France 71% 10 NR OxOnc East Asian 69% % EUCROSS 29 Europe 66% NR * Crizotinib USA and EMA approved in 2016 for ROS treatment 1.Shaw AT, et al. N Engl J Med 2014; Updated ESMO 2016; abstr 1206PD; 2.- Mazieres J, et al. JCO 2015; 3. Moro- Sibilot ASCO 2015; 4. Goto K. et al. ASCO Sebastian WCLC 2016

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51 PFS (%) Ceritinib in ROS+: A Korean Phase II study N=32 (30 crizotinib-naïve) ORR: 67% DCR: 87% PFS: 20.7 mo All (N=32) NO Prior crizotinib (N=30) DOR 18.4 mo (95%CI 8.0, 18.4) ongoing Months Months #6009: Novel Tyrosine Kinase Inhibitors in Lung Cancer Caicun Zhou Lim SM, et al. ESMO Abstract 1205PD; Cho et al. WCLC 2016, J Thorac Oncol 2016; 11(suppl): abstr MA Median OS was not reached by time of data cut-off Signs of intracraneal activity (RR 2/8) Seven ROS fusion partners identified (CD74, SLC34A2, ROS1-EZR)

52 Lorlatinib in Ros+ NSCLC ROS1-positive NSCLC Overall response (n=12) Intracranial (target + non-target lesions)* (n=7) Intracranial (target lesions)* (n=5) Best Overall Response, n (%) Complete response 0 2 (29) 2 (40) Partial response 6 (50) 2 (29) 2 (40) Stable disease 2 (17) 0 0 Progressive disease 3 (25) 2 (29) 0 Indeterminate 1 (8) 1 (14) 1 (20) Objective Response Rate, n (%) 6 (50) 95% CI 21.1, 78.9 Median PFS, months % CI 1.4, 13.9 Median Duration of Response, months % CI 5.7, NR 4 (57) 18.4, (80) 28.4, 99.5 ALK, anaplastic lymphoma kinase; CR, confirmed response; CI, confidence interval; NR, not reached; PFS, progression-free survival; ROS1, c-ros oncogene 56 Felip et al. WCLC 2016

53 BRAF M+ Dabraf + Trame Carbo-alimta- Pembrolizumab Chemo 57

54 Translating Genomic Profiling Data into Therapeutic Strategies (Lung Adenocarcinoma) RET: Cabozantinib : RR=40% HER2 mutation ROS1: 70% RR to Crizotinib ALK: 65%RR to Crizotinib: ~70% RR to 2 Gen TKI Ceritinib in resistant cancers HER2 mutation: >50% RR to Afatinib; ~20% to Dacomitinib BRAF (V600E): >60% RR to BRAF + MEK inhibitor combo METex14: RR >50% to Crizotinib EGFR: RR>70% to 1-2 Gen TKIs; ~60% RR to 3 Gen TKIs in resistant cancers KRAS: 35% RR to MEK inhibitors + Chemotherapy

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56 The technology challenge Planchard D, et al. ASCO 2017

57 Let s say we incorporate a simple NGS panel in our daily clinical practice Regulatory involvement, clinical and analytical validation. Urgent need for accelerated approvals for highly active novel agents: Registry mechanisms, national basadate Only 5% of patients get access to clinical trials. NGS in French experience allowed enrichment of inclusion in clinical trials (57%) or expanded access programs (23%) (Plancard et al. Eur J Cancer 2015) EAP Large genomic trials (basket or umbrella trials) geographic distribution? Early phase centers network We need: Collaborative efforts across centers Registers listing recruiting clinical trials Patients need to be prepared to travel GENEROSITY NO PERSONALISMS

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